M918V RET mutation causes familial medullary thyroid carcinoma: study of 8 affected kindreds.

Abstract:

:Germline mutations in codon 918 of exon 16 of the RET gene (M918T) are classically associated with multiple endocrine neoplasia type 2B (MEN 2B) with highly aggressive medullary thyroid cancer (MTC), pheochromocytoma and a unique phenotype. The objectives of this study are to describe the rare M918V RET mutation discovered in 8 MTC kindreds from Brazil lacking the MEN 2B phenotype classically observed in M918T patients and to investigate the presence of a founder effect for this germline mutation. Eight apparently sporadic MTC cases were diagnosed with the germline M918V RET mutation. Subsequently, their relatives underwent clinical and genetic assessment (n = 113), and M918V was found in 42 of them. Until today, 20/50 M918V carriers underwent thyroidectomy and all presented MTC/C-cell hyperplasia; the remainder carriers are on clinical follow-up. None of the M918V carriers presented clinical features of MEN 2B. Their clinical presentation was heterogeneous, and the age at tumor diagnosis ranged from 24 to 59 years. Lymph node metastases were present in 12/20 patients, and presumable distant metastases in 2/20; in contrast, we observed a carrier of up to 87 years of age without evidence of MTC. Ethnographic fieldwork and haplotype analyses suggested that the founder mutation first settled in that area fifteen generations ago and originated from Portugal. Our study is the first to demonstrate the RET M918V mutation co-segregating in 8 familial MTC kindreds with validated evidence of a founder effect. We suggest that M918V MTC should be clinically considered an American Thyroid Association (ATA) moderate-risk category.

journal_name

Endocr Relat Cancer

journal_title

Endocrine-related cancer

authors

Martins-Costa MC,Cunha LL,Lindsey SC,Camacho CP,Dotto RP,Furuzawa GK,Sousa MS,Kasamatsu TS,Kunii IS,Martins MM,Machado AL,Martins JR,Dias-da-Silva MR,Maciel RM

doi

10.1530/ERC-16-0141

subject

Has Abstract

pub_date

2016-12-01 00:00:00

pages

909-920

issue

12

eissn

1351-0088

issn

1479-6821

pii

23/12/909

journal_volume

23

pub_type

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